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Biological Research

Print version ISSN 0716-9760

Biol. Res. vol.37 no.4 Santiago  2004

http://dx.doi.org/10.4067/S0716-97602004000400013 

 

Biol Res 37: 593-602, 2004

ARTICLE

Modulation of cytosolic calcium signaling by protein kinase A-mediated phosphorylation of inositol 1,4,5-trisphosphate receptors

STEPHEN V. STRAUB, LARRY E. WAGNER II, JASON I.E. BRUCE and DAVID I. YULE

University of Rochester, Department of Pharmacology and Physiology, Rochester, New York 14642 USA

Dirección para Correspondencia


ABSTRACT

Calcium release via intracellular Ca2+ release channels is a central event underpinning the generation of numerous, often divergent physiological processes. In electrically non-excitable cells, this Ca2+ release is brought about primarily through activation of inositol 1,4,5-trisphosphate receptors and typically takes the form of calcium oscillations. It is widely believed that information is carried in the temporal and spatial characteristics of these signals. Furthermore, stimulation of individual cells with different agonists can generate Ca2+ oscillations with dramatically different spatial and temporal characteristics. Thus, mechanisms must exist for the acute regulation of Ca2+ release such that agonist-specific Ca2+ signals can be generated. One such mechanism by which Ca2+ signals can be modulated is through simultaneous activation of multiple second messenger pathways. For example, activation of both the InsP3 and cAMP pathways leads to the modulation of Ca2+ release through protein kinase A mediated phosphoregulation of the InsP3R. Indeed, each InsP3R subtype is a potential substrate for PKA, although the functional consequences of this phosphorylation are not clear. This review will focus on recent advances in our understanding of phosphoregulation of InsP3R, as well as the functional consequences of this modulation in terms of eliciting specific cellular events.

Key words: Inositol 1,4,5-trisphosphate receptor, protein kinase A, calcium signaling, pancreatic acinar cells, parotid acinar cells.


SPECIFIC ACTIVATION OF DISTINCT CELLULAR PROCESSES IS ENCODED IN THE SPATIAL AND TEMPORAL CHARACTERISTICS OF Ca2+ SIGNALS

Cytosolic calcium is the most versatile signaling molecule in biology. Changes in the concentration of cytosolic Ca2+ ([Ca2+]c) have been found to exert control over a myriad of different cellular processes including, but certainly not limited to, increases in gene transcription (Dolmetsch et al., 1997; Dolmetsch et al., 2001), muscle contraction (Jaggar et al., 2000), and exocytosis (Augustine, 2001). In addition, [Ca2+]c changes are involved in exerting control over a number of opposing physiological processes, including smooth muscle contraction and relaxation (Jaggar et al., 2000), as well as mitochondrial metabolism and apoptotic cell death (Gunter and Gunter, 2001). The control of such a diverse array of cellular functions by a single messenger suggests that specificity to exert control upon an individual effector must exist within the signal transduction system. Indeed, the Ca2+ signal itself appears uniquely suited to encode specific information, as diverse Ca2+ signals, displaying a wide range of temporal and spatial characteristics, can be generated in a given cell (Cuthbertson et al., 1981; Cuthbertson and Cobbold, 1985; Woods et al., 1986; Woods et al., 1987). Thus, Ca2+ signals with a particular spatial and temporal "signature" could potentially underlie the generation of a specific, singular cellular process. Indeed, this assertion has been confirmed in numerous studies to date. For example, it has been shown that Ca2+ oscillations of a particular frequency are capable of selectively eliciting the activation Ca2+-calmodulin-dependent protein kinase II (De Koninck and Schulman, 1998), while spatially localized Ca2+ signals, such as Ca2+ influx through L-type Ca2+ channels in neurons, are effective at activating transcription factors such as CREB and MEF-2 due to spatial targeting of Ca2+-sensitive signal transduction components in the vicinity of the L-channels (Dolmetsch et al., 2001). Therefore, the ability to generate a variety of Ca2+ signals allows for the selective modulation of a myriad of cellular effects by a singular signaling molecule (Berridge et al., 2000). Thus, the mechanisms by which Ca2+ release events are modulated, such that diverse signaling patterns can be generated, are integral to the universality and specificity inherent in Ca2+ signaling.

PHOSPHOREGULATION OF Ca2+ RELEASE FROM InsP3R

In most electrically non-excitable cells, such as hepatocytes and the exocrine cells of the pancreas and parotid salivary gland, Ca2+ release from InsP3R is the major mechanism by which [Ca2+]c changes are brought about (Thomas et al., 1996; Bird et al., 1998). Therefore, regulation of Ca2+ release at the level of the InsP3R is potentially of importance in allowing the cell to generate a multitude of Ca2+ signaling patterns. Three subtypes of InsP3R are expressed in mammalian cells, type I, II, and III (Furuichi et al., 1989a; Furuichi et al., 1989b; Sudhof et al., 1991; Thomas et al., 1996; Patel et al., 1999). In addition, multiple splice variants of the receptors exist. For example, the type I InsP3R can be spliced at three distinct regions, denoted as SI-SIII, with five unique variants resulting from splicing at the SII site. In terms of expression, two splice variants of the type I receptor appear to predominate. The SII+ isoform, also known as the long or neuronal form, is expressed primarily in neuronal tissues, while the SII- isoform (short form) is expressed primarily in the periphery. Each functional receptor exists as a tetrameric assembly of similar or dissimilar subunits, thus allowing for the formation of homo- or hetero-tetramers. The N-terminal 600 amino acids of each subunit comprise a binding region for InsP3. Giving the critical requirement for a number of amino acid residues in different regions of this N-terminus, it is believed that the three-dimensional structure of the N-terminus forms a binding pocket for InsP3. The C-terminal region of the protein comprises the channel domain and, along with the N-terminus, shows high sequence homology across subtypes and species (Patel et al., 1999).

A primary distinction between receptor subtypes is the differential sensitivity to activation by InsP3 and Ca2+. Activation of each subtype requires the binding of InsP3, but Ca2+ itself acts as a co-agonist of the receptor (Kaftan et al., 1997; see also Foskett and Mak, 2004, this issue). Indeed, the binding of calcium to an activation site is thought to be required for channel activation under physiological conditions (Mak et al., 2001). Thus, the distinct InsP3 and Ca2+ sensitivities may result in each subtype being uniquely suited to generate Ca2+ signals in different cellular environments. For example, the type III InsP3R has been proposed to act as a trigger for Ca2+ release events, given a less significant effect of Ca2+ inhibition on this subtype (Hagar et al., 1998), as well as an enhanced sensitivity to activation by near resting Ca2+ levels. While each receptor subtype possesses an inherently different sensitivity to InsP3 and Ca2+, the primary difference between receptor subtypes at the amino acid level, and perhaps functionally as well, exists in the large regulatory domain, which spans the region between the N- and C-termini, and comprises the majority of the protein, being approximately 1600 amino acids in length (Patel et al., 1999). This region contains sites for potential interactions with a range of regulatory factors, including Ca2+, ATP, regulatory proteins such as CaM and FKBP, as well as sites for phosphorylation by a range of protein kinases, including PKA, PKG, CaM-kinase, and PKC. Each subtype appears to have a unique susceptibility to modulation, and similar modulatory events appear to have the capacity to evoke different effects dependent upon the receptor subtype involved.

Phosphorylation of InsP3R has been extensively examined in the type I InsP3R, particularly in terms of the effects of PKA phosphorylation on Ca2+ release from this subtype (Supattapone et al., 1988; Ferris et al., 1991; Wojcikiewicz and Luo, 1998; Tang et al., 2003). Despite this intensive investigation, a consensus does not exist as to the effects of this phosphorylation, although recent findings have enhanced our understanding of this phenomenon. Initial experiments investigating PKA-mediated phosphorylation of type I InsP3R performed by Ross and colleagues suggested that two PKA phosphorylation sites exist in the type I receptor, at serines 1589 and 1755 (Ferris et al., 1991). Interestingly, serine 1589 was suggested to be phosphorylated in the SII- (short, peripheral) splice variant, while serine 1755 was phosphorylated in the SII+ (long, neuronal) form of the receptor. In a subsequent study, Snyder and colleagues found that PKA phosphorylation of InsP3R purified from cerebellum (SII+) resulted in 10-fold decrease in the sensitivity of the receptor to InsP3, measured as a decrease in 45Ca2+ flux from microsomal vesicles (Supattapone et al., 1988). In contrast, studies from Wojcikiewicz and Luo suggested that PKA phosphorylation of the SII+ splice variant, presumably at serine 1755, resulted in a modest 20% increase in the sensitivity of the receptor to InsP3, as measured in permeabilized SH-SY5Y neuroblastoma cells (Wojcikiewicz and Luo, 1998). Compared to the neuronal form of the receptor, there has been much less investigation of effects of phosphorylation on the SII- splice variant. One elegant study performed by Tertyshnikova and Fein suggested that PKA phosphorylation of this InsP3R resulted in decreased Ca2+ release in response to photorelease of caged InsP3 in megakaryocytes. This effect on Ca2+ release was not due to effects of PKA on Ca2+ clearance (Tertyshnikova and Fein, 1998).

One difficulty in defining the effects of phosphorylation on a particular InsP3R subtype is that obtaining a completely pure InsP3R population is difficult, since most cell types express more than one subtype of InsP3R. This is one reason much attention has focused on the SII+ form of the type I InsP3R, since cerebellum expresses greater than 99% type I InsP3R. Even so, discrepancies clearly exist in terms of the effects of phosphorylation on this splice variant. To investigate other InsP3R subtypes, various studies have utilized cell lines that express predominantly one InsP3R isoform. For example, AR4-2J cells express > 88% type II InsP3R, while RINm5F cells express > 96% type III InsP3R (Wojcikiewicz and Luo, 1998). Although use of these cell lines is still complicated by the fact that multiple receptor subtypes are expressed, until recently these systems have been one of the most direct ways to investigate individual InsP3R subtypes.

A major advance in the study of InsP3R regulation was the generation of a triple InsP3R knockout cell line by Kurosaki and colleagues, which functions as the only known null background for InsP3R (Sugawara et al., 1997). Our lab has utilized this DT40 chicken B-cell line to dissect the molecular loci and functional consequences of PKA phosphorylation on both major splice variants of the type I InsP3R. Transient transfection of the InsP3R of interest allows for the study of this receptor in the complete absence of all other InsP3R subtypes, thus allowing for the study of individual subtypes as well as receptors containing mutations of interest. In cells transfected with the SII+ type I InsP3R, as well as M3 muscarinic receptor and the fluorescent indicator protein HcRed, stimulation with low (nM) concentrations of carbachol (CCh) elicited increases in [Ca2+]c, as measured by fura-2 fluorescence (Fig. 1A) (Wagner et al., 2003). Treatment of cells with forskolin, to raise cellular levels of cAMP and activate PKA, resulted in an enhanced [Ca2+]c increase upon subsequent exposure to agonist. Consistent with previous studies which indicated that serine 1755 was the residue phosphorylated in the neuronal form of the receptor, our studies found that this increased sensitivity to agonist was dependent upon phosphorylation of serine 1755, as [Ca2+]c increases in cells expressing a receptor containing an S1755A point mutation were not affected by forskolin treatment (Fig. 1B). In addition, expression of receptors containing an S1589A mutation still showed the same level of potentiation of the [Ca2+]c signal following forskolin treatment as did wild type SII+ receptors (Fig. 1E), suggesting that in the long form of the type I receptor, phosphorylation of serine 1589 is functionally insignificant in terms of effects on Ca2+ release. In contrast, in the peripheral (SII-) form of the type I receptor, phosphorylation of either S1589 or S1755 resulted in enhanced Ca2+ release (Fig. 1 C-D,F), suggesting that in this form of the receptor, both potential phosphorylation sites are functionally important. Thus, utilization of the triple InsP3R knockout DT40 cell line allows for the effects of potential modulatory events occurring at the level of the InsP3R to be studied with InsP3R populations of unambiguous composition, as well as InsP3R of altered molecular composition.

 

 

Figure 1. Investigation of PKA-mediated phosphorylation of type I InsP3R expressed in DT40 cells. A) Fura-2 loaded triple InsP3R knockout DT40 cells expressing the SII+ (neuronal) form of the type I InsP3R and M3 muscarinic receptor were stimulated with CCh to elicit an elevation of [Ca2+]c. Only cells positively identified as transfected, as detected by HcRed expression, responded to agonist (black trace). Exposure of cells to forskolin to activate PKA resulted in a potentiated [Ca2+]c increase compared to the control response. B) Mutation of serine 1755 to alanine in the SII+ receptor prevented the effect of PKA activation on the [Ca2+]c increase, suggesting that phosphorylation of this residue is critical in mediating the effects of PKA phosphorylation on this form of the type I receptor. C) [Ca2+]c increases elicited by CCh stimulation prior to and following exposure to forskolin in DT40 expressing the SII- (peripheral) form of type I InsP3R. D) Mutation of both serine residues (1589 and 1755) in the SII- receptor was required in order to inhibit potentiation of the [Ca2+]c increase following PKA activation, suggesting both residues are functionally important for altering Ca2+ release in this form of the receptor. E) Pooled data showing the fold increase in [Ca2+]c (normalized to the control response) following exposure to forskolin for wild type SII+, S1589A and S1755A point mutants of the type I InsP3R. F) Pooled data showing fold increase in [Ca2+]c elicited following treatment with forskolin and CCh (normalized to control) for cells expressing wild type SII-, S1589A or S1755A single point mutants and double (S1589A, S1755A) mutant InsP3R. Adapted from Wagner et al., 2003, with permission. © (2003) The American Society for Biochemistry and Molecular Biology.

 

SPECIFIC PHYSIOLOGICAL OUTCOMES GENERATED BY InsP3R PHOSPHORYLATION IN NON-EXCITABLE CELLS

While the use of heterologous expression systems is helpful in determining the effect of InsP3R phosphorylation on Ca2+ release from the channel, receptor modulation in the context of a biological system is likely to have consequences beyond simply altering the rate or magnitude of Ca2+ release. Consistent with this assertion, we have found that InsP3R phosphorylation may be involved in modulating physiological processes in exocrine acinar cells of the pancreas and parotid salivary gland (Bruce et al., 2002; Straub et al., 2002). In parotid acinar cells, where the major physiological function is fluid secretion leading to the generation of the primary saliva, it is known that maximal secretion occurs following stimulation of both sympathetic and parasympathetic pathways (Bobyock and Chernick, 1989; Larsson and Olgart, 1989). Elevation of cAMP was found to result in the generation of a [Ca2+]c signal in response to a previously sub-threshold concentration of agonist, and the conversion of an oscillatory [Ca2+]c signal into a peak-and-plateau type response (Fig. 2 A) (Bruce et al., 2002), suggesting an increased sensitivity of the signal transduction machinery to agonist. This increased sensitivity was not due to a change in the activity of Ca2+ clearance mechanisms, or effects on InsP3 production, Ca2+ influx or release from ryanodine receptors, but rather due to a direct effect on InsP3R, as Ca2+ release evoked by InsP3 was enhanced following elevation of cAMP in permeabilized parotid cells (Bruce et al., 2002).

Similar to most cell types, parotid cells express all three InsP3R subtypes with the types II and III comprising the majority of receptors and the type I accounting for only 5% of the receptor population (Zhang et al., 1999; Giovannucci et al., 2002). Phosphorylation appears to occur at the level of the type II receptor in this system, as robust phosphorylation was found in immunoprecipitated type II InsP3R following treatment of cells with forskolin (Bruce et al., 2002). This finding of potentiated Ca2+ release following phosphorylation of the type II InsP3R is consistent with early literature from hepatocytes showing similar effects of type II phosphorylation by PKA (Hajnoczky et al., 1993). In parotid, the effector for the enhanced Ca2+ release generated during peak secretion is likely to be one or more plasma membrane resident Ca2+-activated ion channels involved in the generation of a transcellular osmotic gradient responsible for fluid movement (Iwatsuki et al., 1985; Kasai and Augustine, 1990). Following a [Ca2+]c increase, Ca2+-activated Cl- channels present on the apical membrane become activated due to the close association between these channels and the InsP3R, the majority of which are present in the apical region of the cell (Kasai and Augustine, 1990). Activation of these channels leads to Cl- efflux from the cell into the lumen, establishing an osmotic gradient, which results in the paracellular movement of Na+ and water. The potentiated Ca2+ signal is also likely to enhance the activity of Ca2+-activated K+ channels, present on the basolateral membrane, which function to reverse membrane depolarization resulting from Cl- efflux. Thus, the PKA-mediated potentiation of InsP3-evoked Ca2+ release is able to enhance fluid secretion by altering the activity of the Ca2+ sensitive secretory machinery.

Figure 2. Functional effects of InsP3R phosphorylation in exocrine cells. A) Fura-2 loaded parotid acinar cells were stimulated with sub-threshold (30 nM) and oscillatory (100 nM) concentrations of CCh to elicit an increase in [Ca2+]c. [Ca2+]c increases in the apical region of the cell are noted with an arrow while [Ca2+]c changes in the basal region are shown in the unlabeled trace. Exposure to forskolin was found to enhance the CCh-evoked [Ca2+]c increase, such that previously sub-threshold concentrations of agonist now evoked oscillations while previously oscillatory agonist concentrations now evoked a peak-and-plateau type response. B) Stimulation of pancreatic acinar cells with CCh or CCK evokes dramatically different patterns of [Ca2+]c oscillations in fura-2-loaded cells. One characteristic difference between the [Ca2+]c increases elicited by these agonists is the kinetics of the rising phase of the [Ca2+]c oscillations. This difference in the [Ca2+]c responses was found to be due to the PKA-mediated phosphorylation of type III InsP3R produced during stimulation with CCK. C) Whole cell patch clamped, fura-2 loaded pancreatic acinar cells were stimulated with CCK, evoking the typical pattern of baseline [Ca2+]c oscillations associated with this agonist. D) Inclusion of HT31 in the patch pipette, to disrupt the targeting of PKA to AKAP and inhibit the effects of a targeted PKA-mediated phosphorylation event, resulted in a disruption in the normal pattern of oscillations evoked by CCK stimulation. Adapted from Bruce et al., 2002, and Straub et al., 2002, with permission. © (2002) The American Society for Biochemistry and Molecular Biology.

In pancreatic acinar cells, there exists a situation similar to that in parotid acinar cells: the type II and III InsP3R comprise the majority of the InsP3R population, while type I receptors make up less than 3% of the receptor complement (Wojcikiewicz, 1995). However, in the pancreas the physiologically relevant phosphorylation event appears to occur at the level of the type III receptor (Straub et al., 2002). In these cells, Ca2+ signals are generated in response to a wide range of agonists, and it is well documented that stimulation with different agonists results in the generation of agonist-specific [Ca2+]c signaling patterns (Fig. 2B) (Yule et al.; see also Petersen, this issue). In particular, stimulation with acetylcholine (ACh) results in the generation of frequent [Ca2+]c oscillations (4-6/min) which are superimposed upon an elevated [Ca2+]c plateau, while stimulation with the hormone cholecystokinin (CCK) results in the generation of infrequent oscillations (1/min) which are generated from the baseline [Ca2+]c level, and are thus termed baseline [Ca2+]c oscillations. The agonists appear to utilize similar signal transduction machinery to generate [Ca2+]c signals, as inhibition of the Gq family of heterotrimeric G proteins (Yule et al., 1999) or of Ca2+ release from InsP3R (Thorn et al., 1994; Cancela et al., 1999) prevents [Ca2+]c increases from these agonists. Thus, an agonist specific modulation of a common signal transduction component appeared to be involved in the generation of [Ca2+]c signals to one or both of these agonists. Previous studies had shown that CCK receptors were capable of coupling to Gq as well as Gs family G proteins (Schnefel et al., 1990) and that stimulation with supraphysiological CCK concentrations resulted in the formation of cAMP and activation of PKA (Marino et al., 1993). Thus, we hypothesized that CCK stimulation could result in the PKA-mediated phosphorylation of InsP3R, leading to an alteration of Ca2+ release compared to that which occurs during stimulation with ACh. Consistent with this, it was found that stimulation of acinar cells with physiological concentrations of CCK, which result in baseline [Ca2+]c oscillations, evoked phosphorylation of type III InsP3R which was dependent upon activation of PKA (LeBeau et al., 1999; Straub et al., 2002). Interestingly, stimulation with ACh did not evoke receptor phosphorylation at agonist concentrations which generate [Ca2+]c oscillations. In terms of functional effects on Ca2+ release and the characteristics of the evoked [Ca2+]c signal, phosphorylation of the type III receptor was found to slow the rising phase of [Ca2+]c increases evoked by ACh stimulation or photorelease of caged InsP3, and this slowing in the kinetics of Ca2+ release was found to mimic the difference in the rising phase of [Ca2+]c increases evoked by CCK and ACh (Fig 2B) (Straub et al., 2002). Furthermore, activation of PKA during a train of Ach-evoked oscillations was found to decrease the frequency and maximal amplitude of the oscillations (Giovannucci et al., 2000).

Since all three InsP3R subtypes are expressed in parotid and pancreatic acinar cells, and all three subtypes have been shown to be substrates for InsP3R phosphorylation, how is it that a particular subtype is preferentially phosphorylated by PKA? In addition to a cytosolic localization, PKA can also be localized to its substrate through binding to a family of scaffolding proteins known as A kinase anchoring proteins, or AKAPs (Colledge and Scott, 1999). These proteins comprise a growing family of functionally similar but structurally diverse proteins, which, in addition to binding PKA, can form macromolecular complexes containing PKA, several protein phosphatases such as PP1 and PP2A, as well as the substrate for PKA phosphorylation. Each AKAP contains a targeting domain, which directs the protein to a particular subcellular region, allowing PKA to function as a spatially targeted kinase. Thus, targeting of PKA to a particular InsP3R subtype through binding of an AKAP directly to the channel, or to a docking site in the vicinity of the channel, would allow for the selective phosphorylation of a particular InsP3R subtype. The binding of PKA to an AKAP occurs through multiple physical interactions between amphipathic helices present in both the RII regulatory subunits of PKA and the AKAP and can be selectively disrupted by peptide known as HT31, which contains the RII binding site from an AKAP expressed in human thyroid (Colledge and Scott, 1999). This peptide can be utilized to dissect the effects of PKA which are due to a targeted kinase versus those effects due to cytosolic PKA. When HT31 was introduced into pancreatic acinar cells via diffusion through a patch clamp pipette, it was found that the typical pattern of baseline oscillations normally associated with CCK stimulation was severely disrupted, such that the oscillations were now elicited upon an elevated [Ca2+]c plateau (Fig. 2C, D) (Straub et al., 2002). Interestingly, HT31 was without effect on oscillations evoked by ACh stimulation, suggesting that a targeted, PKA-mediated phosphorylation event, presumably occurring at the level of the type III InsP3R, is involved in generating the physiological pattern of [Ca2+]c oscillations associated with CCK stimulation in pancreatic acinar cells. Furthermore, it was found that stimulation with another agonist, bombesin, which activates neuromedin-type receptors and evokes a baseline pattern of [Ca2+]c oscillations similar to those evoked by CCK, also elicited phosphorylation of type III InsP 3R which was again dependent upon activation of PKA (Straub et al., 2002). These findings suggest that PKA-mediated phosphorylation of InsP3R may be part of a general mechanism by which a baseline pattern of [Ca2+]c oscillations is evoked in pancreatic acinar cells.

CONCLUSIONS

Overall, these findings highlight one potential mechanism by which InsP3-evoked Ca2+ signals can be shaped such that an array of physiological outcomes can be achieved with a high degree of specificity. Utilization of the DT40 cell line will allow for the dissection of the molecular loci at which phosphorylation occurs in type II and III InsP3R, as well as for a determination of the functional consequences of these phosphorylation events. These findings will be utilized to enhance our understanding of the mechanisms by which crosstalk between the Ca2+ signaling and cAMP pathways contributes to the generation of specific physiological processes in primary tissues.

ACKNOWLEDGEMENTS

The authors would like to thank Dr. Trevor J. Shuttleworth for helpful comments on the manuscript. D.I.Y. is supported by grants from NIH (RO1-DK54568, RO1-DE14756, and PO1-DE13539). S.V.S. is supported by an NIH training grant through NIDCR (T32-DE007202).

REFERENCES

AUGUSTINE GJ (2001) How does calcium trigger neurotransmitter release? Curr Opin Neurobiol 11:320-326         [ Links ]

BERRIDGE MJ, LIPP P, BOOTMAN MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1:11-21         [ Links ]

BIRD GS, LOUZAO MC, RIBEIRO CM, PUTNEY JW JR (1998) Calcium signalling in exocrine glands. Euro J Morphol 36 Suppl:153-156         [ Links ]

BOBYOCK E, HERNICK WS (1989) Vasoactive intestinal peptide interacts with alpha-adrenergic-, cholinergic-, and substance-P-mediated responses in rat parotid and submandibular glands. J Dent Res 68:1489-1494         [ Links ]

BRUCE JI, SHUTTLEWORTH TJ, GIOVANNUCCI DR, YULE DI (2002) Phosphorylation of inositol 1,4,5-trisphosphate receptors in parotid acinar cells. A mechanism for the synergistic effects of cAMP on Ca2+ signaling. J Biol Chem 277:1340-1348         [ Links ]

CANCELA JM, CHURCHILL GC, GALIONE A (1999) Coordination of agonist-induced Ca2+-signalling patterns by NAADP in pancreatic acinar cells. Nature 398:74-76         [ Links ]

COLLEDGE M, SCOTT JD (1999) AKAPs: From structure to function. Trends Cell Biol 9:216-221         [ Links ]

CUTHBERTSON KS, COBBOLD PH (1985) Phorbol ester and sperm activate mouse oocytes by inducing sustained oscillations in cell Ca2+. Nature. 316:541-542.         [ Links ]

CUTHBERTSON KS, WHITTINGHAM DG, COBBOLD PH (1981) Free Ca2+ increases in exponential phases during mouse oocyte activation. Nature 294:754-757         [ Links ]

DE KONINCK P, SCHULMAN H (1998) Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Sci 279:227-230         [ Links ]

DOLMETSCH RE, LEWIS RS, GOODNOW CC, HEALY JI (1997) Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386:855-858         [ Links ]

DOLMETSCH RE, PAJVANI U, FIFE K, SPOTTS JM, GREENBERG ME (2001) Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Sci 294:333-339         [ Links ]

FERRIS CD, CAMERON AM, BREDT DS, HUGANIR RL, SNYDER SH (1991) Inositol 1,4,5-trisphosphate receptor is phosphorylated by cyclic AMP-dependent protein kinase at serines 1755 and 1589. Biochem Biophys Res Commun 175:192-198         [ Links ]

FOSKETT KE, MAK DOD (2004) Novel model of inositol 1,4,5-trisphosphate regulation of InsP3 receptor channel gating in native endoplasmic reticulum. Biol Res 37: 513-519         [ Links ]

FURUICHI T, YOSHIKAWA S, MIKOSHIBA K (1989a) Nucleotide sequence of cDNA encoding P400 protein in the mouse cerebellum. Nucleic Acids Res 17:5385-5386         [ Links ]

FURUICHI T, YOSHIKAWA S, MIYAWAKI A, WADA K, MAEDA N, MIKOSHIBA K (1989b) Primary structure and functional expression of the inositol 1,4,5-trisphosphate-binding protein P400. Nature. 342:32-38         [ Links ]

GIOVANNUCCI DR, BRUCE JI, STRAUB SV, ARREOLA J, SNEYD J, SHUTTLEWORTH TJ, YULE DI (2002) Cytosolic Ca(2+) and Ca(2+)-activated Cl(-) current dynamics: insights from two functionally distinct mouse exocrine cells. J Physiol 540:469-484         [ Links ]

GIOVANNUCCI DR, GROBLEWSKI GE, SNEYD J, YULE DI (2000) Targeted phosphorylation of inositol 1,4,5-trisphosphate receptors selectively inhibits localized Ca2+ release and shapes oscillatory Ca2+ signals. J Biol Chem 275:33704-33711         [ Links ]

GUNTER TE, GUNTER KK (2001) Uptake of calcium by mitochondria: Transport and possible function. IUBMB Life 52:197-204         [ Links ]

HAGAR RE, BURGSTAHLER AD, NATHANSON MH, EHRLICH BE (1998) Type III InsP3 receptor channel stays open in the presence of increased calcium. Nature 396:81-84         [ Links ]

HAJNOCZKY G, GAO E, NOMURA T, HOEK JB, THOMAS AP (1993) Multiple mechanisms by which protein kinase A potentiates inositol 1,4,5-trisphosphate-induced Ca2+ mobilization in permeabilized hepatocytes. Biochem J 293 (Pt 2):413-422         [ Links ]

IWATSUKI N, MARUYAMA Y, MATSUMOTO O, NISHIYAMA A (1985) Activation of Ca2+-dependent Cl- and K+ conductances in rat and mouse parotid acinar cells. Jpn J Physiol 35:933-944         [ Links ]

JAGGAR JH, PORTER VA, LEDERER WJ, NELSON MT (2000) Calcium sparks in smooth muscle. Am J Physiol Cell Physiol 278:C235-256         [ Links ]

KAFTAN EJ, EHRLICH BE, WATRAS J (1997) Inositol 1,4,5-trisphosphate (InsP3) and calcium interact to increase the dynamic range of InsP3 receptor-dependent calcium signaling. J Gen Physiol 110:529-538         [ Links ]KASAI H, AUGUSTINE GJ (1990) Cytosolic Ca2+ gradients triggering unidirectional fluid secretion from exocrine pancreas. Nature 348:735-738         [ Links ]

LARSSON O, OLGART L (1989) The enhancement of carbachol-induced salivary secretion by VIP and CGRP in rat parotid gland is mimicked by forskolin. Acta Physiol Scand 137:231-236         [ Links ]

LEBEAU AP, YULE DI, GROBLEWSKI GE, SNEYD J (1999) Agonist-dependent phosphorylation of the inositol 1,4,5-trisphosphate receptor: A possible mechanism for agonist-specific calcium oscillations in pancreatic acinar cells. J Gen Physiol 113:851-872         [ Links ]

MAK DO, MCBRIDE S, FOSKETT JK (2001) Regulation by Ca2+ and inositol 1,4,5-trisphosphate (InsP3) of single recombinant type 3 InsP3 receptor channels. Ca2+ activation uniquely distinguishes types 1 and 3 insp3 receptors. J Gen Physiol 117:435-446         [ Links ]

MARINO CR, LEACH SD, SCHAEFER JF, MILLER LJ, GORELICK FS (1993) Characterization of cAMP-dependent protein kinase activation by CCK in rat pancreas. FEBS Lett 316:48-52         [ Links ]

PATEL S, JOSEPH SK, THOMAS AP (1999) Molecular properties of inositol 1,4,5-trisphosphate receptors. Cell Calcium 25:247-264         [ Links ]

SCHNEFEL S, PROFROCK A, HINSCH KD, SCHULZ I (1990) Cholecystokinin activates Gi1-, Gi2-, Gi3- and several Gs-proteins in rat pancreatic acinar cells. Biochem J 269:483-488         [ Links ]

STRAUB SV, GIOVANNUCCI DR, BRUCE JI, YULE DI (2002) A role for phosphorylation of inositol 1,4,5-trisphosphate receptors in defining calcium signals induced by Peptide agonists in pancreatic acinar cells. J Biol Chem 277:31949-31956         [ Links ]

SUDHOF TC, NEWTON CL, ARCHER BT III, USHKARYOV YA, MIGNERY GA (1991) Structure of a novel InsP3 receptor. Embo J 10:3199-3206         [ Links ]

SUGAWARA H, KUROSAKI M, TAKATA M, KUROSAKI T (1997) Genetic evidence for involvement of type 1, type 2 and type 3 inositol 1,4,5-trisphosphate receptors in signal transduction through the B-cell antigen receptor. Embo J 16:3078-3088         [ Links ]

SUPATTAPONE S, DANOFF SK, THEIBERT A, JOSEPH SK, STEINER J, SNYDER SH (1988) Cyclic AMP-dependent phosphorylation of a brain inositol trisphosphate receptor decreases its release of calcium. Proc Natl Acad Sci USA 85:8747-8750         [ Links ]

TANG TS, TU H, WANG Z, BEZPROZVANNY I (2003) Modulation of type 1 inositol (1,4,5)-trisphosphate receptor function by protein kinase a and protein phosphatase 1alpha. J Neurosci 23:403-415         [ Links ]

TERTYSHNIKOVA S, FEIN A (1998) Inhibition of inositol 1,4,5-trisphosphate-induced Ca2+ release by cAMP-dependent protein kinase in a living cell. Proc Natl Acad Sci USA 95:1613-1617         [ Links ]

THOMAS AP, BIRD GS, HAJNOCZKY G, ROBB-GASPERS LD, PUTNEY JW JR (1996) Spatial and temporal aspects of cellular calcium signaling. FASEB J 10:1505-1517         [ Links ]

THORN P, GERASIMENKO O, PETERSEN OH (1994) Cyclic ADP-ribose regulation of ryanodine receptors involved in agonist evoked cytosolic Ca2+ oscillations in pancreatic acinar cells. EMBO J 13:2038-2043         [ Links ]

WAGNER LE II, LI WH, YULE DI (2003) Phosphorylation of type-1 inositol 1,4,5-trisphosphate receptors by cyclic nucleotide-dependent protein kinases: A mutational analysis of the functionally important sites in the S2+ and S2- splice variants. J Biol Chem 278:45811-45817         [ Links ]

WOJCIKIEWICZ RJ (1995) Type I, II, and III inositol 1,4,5-trisphosphate receptors are unequally susceptible to down-regulation and are expressed in markedly different proportions in different cell types. J Biol Chem 270:11678-11683         [ Links ]

WOJCIKIEWICZ RJ, LUO SG (1998) Phosphorylation of inositol 1,4,5-trisphosphate receptors by cAMP-dependent protein kinase. Type I, II, and III receptors are differentially susceptible to phosphorylation and are phosphorylated in intact cells. J Biol Chem 273:5670-5677         [ Links ]

WOODS NM, CUTHBERTSON KS, COBBOLD PH (1986) Repetitive transient rises in cytoplasmic free calcium in hormone-stimulated hepatocytes. Nature 319:600-602         [ Links ]

WOODS NM, CUTHBERTSON KS, COBBOLD PH (1987) Agonist-induced oscillations in cytoplasmic free calcium concentration in single rat hepatocytes. Cell Calcium 8:79-100         [ Links ]

YULE DI, BAKER CW, WILLIAMS JA (1999) Calcium signaling in rat pancreatic acinar cells: A role for Galphaq, Galpha11, and Galpha14. Am J Physiol 276:G271-279         [ Links ]

YULE DI, LAWRIE AM, GALLACHER DV (1991) Acetylcholine and cholecystokinin induce different patterns of oscillating calcium signals in pancreatic acinar cells. Cell Calcium 12:145-151         [ Links ]

ZHANG X, WEN J, BIDASEE KR, BESCH HR JR, WOJCIKIEWICZ RJ, LEE B, RUBIN RP (1999) Ryanodine and inositol trisphosphate receptors are differentially distributed and expressed in rat parotid gland. Biochem J 340 (Pt 2):519-527         [ Links ]

Corresponding Author: David I. Yule, Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, New York 14642 USA. Phone: (1-585) 273-2154, Fax (1-585) 273-2652, E-mail: David_Yule@urmc.rochester.edu

Received: April 5, 2004. Accepted: May 6, 2004.

 

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